Pemofllla C

Hemophilia C (deficiency of factor X) was described first in 2 sisters and a

maternal uncle of an American Jewish family. All 3 bled after dental extractions,
and the sisters also bled after tonsillectomy. (See Etiology and Epidemiology.)
Even in severe deficiency of factor X, the bleeding tendency is mild. Unlike the
bleeding tendency in hemophilia A or hemophilia B, which is clearly related to
the factor level, the bleeding risk in hemophilia C is not always influenced by
the severity of the deficiency, especially in individuals with partial deficiency.
ndeed, some patients with severe deficiency do not have a bleeding tendency,
whereas some patients with mild deficiency bleed excessively.
This unpredictability, which is not fully understood, makes hemophilia C more
difficult to manage than hemophilia A or B.
Severe deficiency is defined as factor Xc activity of 15-20 U/dL or lower.
Patients with partial deficiency have levels of about 20-60 U/dL (ie, the lower
limit of the normal range). About 30-50% of individuals with partial deficiency
may have excessive bleeding; however, identifying these persons in advance is
difficult. Most individuals with severe deficiency do not spontaneously bleed but
are at risk of bleeding after surgery. Spontaneous bleeding is very rare.
Furthermore, normal infants without hemophilia C are likely to have low factor
Xc levels until they are older than 6 months. (See Etiology and History and
Physical Examination.)
Brenner et al used a logistic regression model to analyze parameters
influencing bleeding tendency in subjects with factor X deficiency from 45
families.
[1]
Odds ratios for bleeding were 13 in homozygotes or double
heterozygotes and 2.6 in heterozygotes. Bleeding was negatively correlated
with the level of factor X, and severe factor X deficiency was a strong predictor
of bleeding. Minor factor X deficiency and blood group O contributed minimally
to bleeding. levels of factor V and von Willebrand factor were not predictors of
bleeding. Bleeding was most common after surgical procedures involving
mucosal membranes.
Other possible explanations for variations in patient bleeding tendencies include
the following:
O Additional clotting factor disorders, especially von Willebrand disease
O Variant factor X molecules (ie, those with a discrepancy between factor X
clotting activity compared with antigen): These variants are rare, and no
correlation between mutation type and bleeding tendency has been identified.
O ncreased fibrinolysis at certain surgical sites:
With regard to the last item, factor X deficiency has been associated with
bleeding problems after surgery or trauma to areas of the body in which the
fibrinolytic activity is particularly high (eg, urogenital tract, oral cavity after dental
extraction or tonsillectomy). Hence, women can present with menorrhagia or
with bleeding related to childbirth or gynecologic surgery. (See History and
Physical Examination and Treatment.)
Go to Acquired Hemophilia, Hemophilia A, and Hemophilia B for complete
information on these topics.
CompIications
Complications of factor X deficiency commonly involve the unpredictable
nature of bleeding.
Patients who receive plasma products may be at risk for contracting unknown,
virally transmissible infections.
Patients with absent factor X may also develop inhibitors to factor X.
n addition, some patients (with preexisting risk factors) who receive factor X
concentrates may be at risk for thrombotic events.
Prognosis
The prognosis is excellent in patients with partial factor X deficiency without
bleeding manifestations.
EtioIogy
The severity of the deficiency is based on plasma factor XC (clotting) activity.
Severe factor X deficiency is present when the activity of factor X in plasma is
less than 1-15 U/dL.
Factor X is a dimeric serine protease, which is composed of chains that each
weigh 80,000 Da. Factor Xa activates factor X and factor X in the original
intrinsic pathway of blood coagulation. Also, thrombin directly activates factor
X, and this direct activation may be more important than the activation due to
factor X. Patients with factor X deficiency, even severe deficiency, do not
necessarily have a tendency to bleed. Hence, the absence of factor X appears
to be irrelevant to factor X.
Factor X is a zymogen that, on activation, undergoes conversion to a serine
protease that leads to activation of factor X, followed by thrombin generation.
The sustained generation of thrombin also leads to the activation of thrombin-
activatable fibrinolysis inhibitor (TAF), which impairs the conversion of
plasminogen to plasmin. Thus, factor X serves as a procoagulant and an
antifibrinolytic agent, and the lack of factor X in plasma results in a tendency to
bleed. People with severe factor X deficiency have a lower incidence of
ischemic stroke.
[2]

Factor X has no role in the complement or kinin pathways but has been shown
to activate fibrinolysis. Alpha-1 antitrypsin is the main inhibitor of factor Xa and
is responsible for two thirds of its inhibition. C1 esterase inhibitor, antithrombin
, and alpha-2 antiplasmin cause the remaining inhibition.
n severe deficiency factor X, bleeding is related to injury, especially when
trauma involves tissues rich in fibrinolytic activators, such as the oral mucosa,
the nose, and the urinary tract. Unlike patients with severe hemophilia A or B,
patients with severe factor X deficiency do not spontaneously bleed.
0n0 mutations
Mutations in the factor X gene cause the congenital deficiency of factor X
clotting activity.
[3]
The inheritance pattern of factor X is autosomal but not
completely recessive, because heterozygotes may have bleeding.
[4]

The gene for factor X is near the gene for prekallikrein on the distal arm of
chromosome 4 (4q35). t is 23 kb, with 15 exons and 14 introns. Factor X is
synthesized in the liver and circulates in the plasma as a complex with high-
molecular-weight kininogen. Factor X has a half-life of about 52 hours.
The first 3 mutations in the factor X gene were described in 6 persons of
Ashkenazi Jewish descent who were severely affected.
More than 200 other mutations that cause factor X deficiency have been
described and are listed in online databases. Databases include Mutations of
Patients with Factor X Deficiency, which is maintained by the University of
North Carolina School of Medicine, and Factorxi.org, an interactive database
maintained by University College London. The published mutations include
missense mutations, nonsense mutations, deletions and/or insertions, and
splice-site mutations. Those described so far are associated mainly with failed
or reduced production of the active protein, and only a few are related to the
production of a dysfunctional molecule.
Four mutations (types -V) have been identified in people of Ashkenazi Jewish
descent. Two of these mutations occur with increased frequency in this
population. Type , which is a nonsense mutation (Glu117stop) is prevalent in
Ashkenazi and raqi Jews. Type , a missense mutation (Phe283Leu), is
present only in Ashkenazi Jews. Homozygotes for type or type mutations
have a factor X activity of 1 and 10 U/dL, respectively, whereas compound
heterozygotes for type or type have factor X activity of 3-5 U/dL.
Various mutations have been identified in persons who are not Jewish. Two
ancestral mutations are described: a mutation with a Cys38Arg substitution in
exon 3 (observed in the French Basque Country) and the mutation C128X in
exon 5 (occurring in England).
[4]
Both mutations result in a factor X level of less
than 1 U/dL in affected homozygotes.
People with mutations leading to absent protein (eg, Glu117Stop, C128X) are
at risk of development of inhibitors (antibodies) to factor X; this should be
considered when selecting treatment for these patients.
Acquired factor X deficiency occurs in patients who develop inhibitors to this
protein, as is sometimes observed in patients with systemic lupus
erythematosus or other immunologic diseases.
Factor X deficiency is a common finding in patients with Noonan syndrome,
which is characterized by congenital cardiac abnormalities, short stature, and
mental retardation.
Epid0mioIogy
Hemophilia C (severe form) occurs with an estimated prevalence of 1 case per
100,000 population in the United States, a rate that makes hemophilia A 10
times more common than hemophilia C.
nternationally, deficiency of factor X is reported in most racial groups, with the
highest frequency in persons of Ashkenazi or raqi Jewish descent
[5, 6]
; in srael,
the estimated rate for heterozygosity is 8%. n the United Kingdom national
database, 1696 patients (many of whom were non-Jewish) with factor X
deficiency were registered in a population of about 60 million (data for 2006),
but most of these have partial deficiency
[7]
; factor X deficiency is more common
than factor X deficiency (hemophilia B). n the French Basque country (home to
the most ancient ethnic group of Western Europe, the Basques), 39 patients
were identified among the general population of 290,000.
[8]

Hemophilia C equally affects males and females.
People of any age group can be affected. Note that normal infants younger than
age 6 months have low levels of factor X because of the time required for
factor X to reach normal levels observed in adults. After this is reached, factor
X levels do not change with age.
Pati0nt Education
Patients must be counseled about the unpredictable nature of their bleeding
tendency, and they should be informed of the preparations needed before
elective surgery.
The usual precautions regarding physical activity for individuals with a bleeding
disorder apply to patients with factor X deficiency who have a bleeding
tendency. Patients should be encouraged to wear seat belts, to use protective
gear (eg, bike helmets), and to avoid contact sports.
Patients should be advised to keep up to date with their vaccinations,
especially hepatitis A virus and hepatitis B virus vaccinations.
Stress the importance of annual visits to hemophilia treatment centers.
Patients should receive genetic counseling with regard to their marriage
partners and the potential risks to their offspring.
CIinicaI findings
Suspect hemophilia C in any patient with a prolonged activated partial
thromboplastin time (aPTT), especially if the family history suggests a mild-to-
moderate lifelong bleeding disorder that affects both male and female
individuals.
Acquired factor X deficiency occurs in patients who develop inhibitors to the
protein, as is sometimes observed in patients with systemic lupus
erythematosus and other immunologic diseases.
Factor X deficiency is described as a common finding in patients with Noonan
syndrome, which is characterized by congenital cardiac abnormalities, short
stature, and mental retardation. These individuals may have other coagulation
defects and should be carefully assessed prior to surgery.
Bleeding after surgery or after injury is the usual presenting symptom in
individuals with hemophilia C.
ndividuals with factor X levels less than 15-20 U/dL are usually at risk of
excessive bleeding after surgery or trauma. Some unusual presentations with
spontaneous bleeding have been reported. n these cases, other pathologic
features may contribute to the bleeding, because spontaneous bleeding is
generally not a feature of hemophilia C. The unusual presentations include the
following:
O Massive hemothorax
O Cerebral hemorrhage
O Subarachnoid hemorrhage
O Spinal epidural hematoma with the Brown-Sequard syndrome
Hematuria and spontaneous hemarthrosis are rare.
n women, menorrhagia is an important finding, and abnormal bleeding after
childbirth may also occur.
Physical findings are usually normal except when bleeding occurs. Bruising
may occur at unusual sites. The patient may have signs of pallor, fatigue, and
tachycardia with excessive bleeding.
orkup
Laboratory studies for suspected hemophilia C should include the following:
O Complete blood count (CBC)
O Measurement of factor X levels
O Measurement of factor V and von Willebrand factor.
O Prothrombin time (PT), aPTT, and thrombin time (TT) (usually performed
before the measurement of factors)
With regard to the last item, the aPTT is usually prolonged in factor X
deficiency (but depends on the sensitivity of the reagent and test system--
partial deficiency can be missed), whereas the PT and TT are normal.
A specific assay for factor X activity is necessary to confirm the diagnosis.
Assays of other clotting factors and platelet function may be needed to exclude
a combined hereditary deficiency of factor X and other factors.
maging studi0s
No imaging studies are necessary in diagnosing factor X deficiency. However,
imaging studies may be obtained to evaluate the extent of bleeding in the
management of bleeding at any site.
0n0tic anaIysis
Genetic analysis for the mutation in factor X is helpful in determining which
mutation caused the deficiency.
Surg|ca| treatment
Treatment of patients with factor X deficiency is a challenge. Patients with
severe deficiency are clearly and commonly at risk of bleeding from surgical
procedures. Bleeding in these patients can start at the time of injury, or it can
be delayed for several hours; it may persist until specific treatment is
administered or it can stop on its own.
Bleeding is much more likely in relation to surgery in areas of high fibrinolytic
activity and is less common in other procedures.
Patients with severe factor X deficiency usually require replacement therapy
before they undergo a surgical procedure, even if they have never bled after
surgery before. Patients with partial deficiency can also have bleeding
episodes, and plans for replacement therapy depend on previous history and
the site of surgery.
Depending on the surgical procedure, the patient's history with other surgical
procedures, and the patient's bleeding tendency, if any, replacement with
plasma products may be needed in the preoperative, intraoperative, and
postoperative periods in patients with hemophilia C.
The management of the patient should be discussed jointly between surgeon,
hematologist and anesthesiologist, and a management plan set out in writing.
Generally, the use of nonsteroidal anti-inflammatory drugs (NSADs) should be
avoided.
Replacement with plasma products must be coordinated with the hemophilia
treatment center.
After a surgical procedure, discharge depends on the type of surgery and how
long replacement therapy is needed, which may be 5-7 days after major
surgery.
The basic principle of management consists of altering the balance between
bleeding and clotting. Therapy consists of replacing the deficient factor and
using other measures, such as fibrin glue and antifibrinolytics.
ng term mn|tr|ng
Annual visits to a hemophilia treatment center are recommended to provide the
following care:
O Monitoring of bleeding episodes
O Planning for any elective surgical procedures
O Monitoring for the development of hepatitis
O Administering preventive immunizations as needed
Continuing patient education about the bleeding condition and applying any
therapeutic advances that may become available.